Sepsis is a common and devastating disease and the leading cause of death in critically ill patients. Microcirculatory failure is a pivotal pathogenic event in sepsis that can play a major role in sepsis-associated organ dysfunction. Our group and others have used orthogonal polarization spectral videomicroscopy, anon- invasive technique of measuring microcirculatory flow indices in human subjects, to demonstrate that impaired microcirculatory flow in sepsis is associated with multi-organ failure and mortality. Currently, there are no novel therapies for sepsis that specifically target the microcirculation. Nitric oxide (NO) maintains microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult as it does in sepsis. Although NO is globally upregulated in sepsis, NO production is heterogeneous between and within organ systems at the microcirculatory level, and some microcirculatory units have low flow. Inhaled nitric oxide (iNO) can deliver NO effectively to the systemic microcirculation and open these low-flow microcirculatory units. We hypothesize that iNO will augment microcirculatory perfusion during sepsis resuscitation with early goal-directed therapy (EGDT), and this increase in microcirculatory flow will result in more effective resuscitation and decreased organ failure. We aim to test this hypothesis with a randomized double-blind placebo-controlled trial to evaluate the ability of iNO to (1) augment microcirculatory perfusion indices during EGDT; and (2) improve two clinically important outcome measures: (a) lactate clearance during EGDT, and (b) the Sequential Organ Failure Assessment score at 24 hours. The overall purpose of this Mentored Patient-Oriented Research Career Development Award is not only to deliver a successful investigation, but more importantly, a successful investigator. The PI's ultimate goal is to develop into an independent investigator who conducts important and innovative clinical trials in patients with circulatory shock. This mentored research training experience will consist of a five-year curriculum specifically focused on clinical trials training. There will be three distinct elements: 1) mentoring, 2) didactic education, and 3) investigation. The mentoring team features a number of renowned experts in sepsis research, including a primary mentor who has conducted NIH-funded research on the microvascular response to sepsis. The PI will train in a rigorous didactic program (Masters of Science in Clinical Epidemiology) and receive formal preparation in the design and analysis of clinical trials. Ultimately, this mentored experience will produce a PI who competes for independent research grants from the NIH. This project will be the first randomized trial specifically targeting the microcirculation in sepsis patients. Given the persistently high morbidity and mortality of sepsis (215,000 deaths annually in the U.S.), this type of clinical trial that uses novel methods to evaluate and treat sepsis has the potential to impact numerous lives and substantially benefit public health.